Landry Natalie M, Dixon Ian M C
Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.
Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.
Cell Signal. 2020 Dec;76:109802. doi: 10.1016/j.cellsig.2020.109802. Epub 2020 Oct 2.
Cardiac fibroblast activation to hyper-synthetic myofibroblasts following a pathological stimulus or in response to a substrate with increased stiffness may be a key tipping point for the evolution of cardiac fibrosis. Cardiac fibrosis per se is associated with progressive loss of heart pump function and is a primary contributor to heart failure. While TGF-β is a common cytokine stimulus associated with fibroblast activation, a druggable target to quell this driver of fibrosis has remained an elusive therapeutic goal due to its ubiquitous use by different cell types and also in the signaling complexity associated with SMADs and other effector pathways. More recently, mechanical stimulus of fibroblastic cells has been revealed as a major point of activation; this includes cardiac fibroblasts. Further, the complexity of TGF-β signaling has been offset by the discovery of members of the SKI family of proteins and their inherent anti-fibrotic properties. In this respect, SKI is a protein that may bind a number of TGF-β associated proteins including SMADs, as well as signaling proteins from other pathways, including Hippo. As SKI is also known to directly deactivate cardiac myofibroblasts to fibroblasts, this mode of action is a putative candidate for further study into the amelioration of cardiac fibrosis. Herein we provide a synthesis of this topic and highlight novel candidate pathways to explore in the treatment of cardiac fibrosis.
在病理刺激后或响应硬度增加的底物时，心脏成纤维细胞激活为高合成性肌成纤维细胞可能是心脏纤维化进展的关键转折点。心脏纤维化本身与心脏泵功能的逐渐丧失相关，并且是心力衰竭的主要促成因素。虽然转化生长因子-β（TGF-β）是与成纤维细胞激活相关的常见细胞因子刺激物，但由于其在不同细胞类型中的广泛使用以及与SMADs和其他效应途径相关的信号复杂性，抑制这种纤维化驱动因素的可药物靶向仍然是一个难以实现的治疗目标。最近，成纤维细胞的机械刺激已被揭示为主要的激活点；这包括心脏成纤维细胞。此外，SKI蛋白家族成员的发现及其固有的抗纤维化特性抵消了TGF-β信号传导的复杂性。在这方面，SKI是一种可能与多种TGF-β相关蛋白结合的蛋白质，包括SMADs，以及来自其他途径的信号蛋白，包括Hippo。由于已知SKI还能直接将心脏肌成纤维细胞失活变回成纤维细胞，这种作用模式是进一步研究改善心脏纤维化的一个假定候选对象。在此，我们对该主题进行了综述，并强调了在治疗心脏纤维化中有待探索的新候选途径。
